Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Critical interactions between TGF-β signaling/ELF, and E-cadherin/β-catenin mediated tumor suppression

Oncogene volume 25, pages 1871–1886 (2006)Cite this article

A Correction to this article was published on 19 April 2021

This article has been updated

Abstract

Inactivation of the transforming growth factor-β (TGF-β) pathway occurs often in malignancies of the gastrointestinal (GI) system. However, only a fraction of sporadic GI tumors exhibit inactivating mutations in early stages of cancer formation, suggesting that other mechanisms play a critical role in the inactivation of this pathway. Here, we show a wide range of GI tumors, including those of the stomach, liver and colon in elf+/− and elf+/−/Smad4+/− mutant mice. We found that embryonic liver fodrin (ELF), a β-Spectrin originally identified in endodermal stem/progenitor cells committed to foregut lineage, possesses potent antioncogenic activity and is frequently inactivated in GI cancers. Specifically, E-cadherin accumulation at cell–cell contacts and E-cadherin-β-catenin-dependent epithelial cell–cell adhesion is disrupted in elf+/−/Smad4+/− mutant gastric epithelial cells, and could be rescued by ectopic expression of full-length elf, but not Smad3 or Smad4. Subcellular fractionation revealed that E-cadherin is expressed mainly at the cell membrane after TGF-β stimulation. In contrast, elf+/−/Smad4+/− mutant tissues showed abnormal distribution of E-cadherin that could be rescued by overexpression of ELF but not Smad3 or Smad4. Our results identify a group of common lethal malignancies in which inactivation of TGF-β signaling, which is essential for tumor suppression, is disrupted by inactivation of the ELF adaptor protein.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 5
Figure 2
Figure 3
Figure 4
Figure 6
Figure 7
Figure 8
Figure 9
Figure 10

Similar content being viewed by others

Change history

Abbreviations

ELF:

embryonic liver fodrin

TGF-β:

transforming growth factor-β

TβRII:

transforming growth factor-β receptor II

TβRI:

transforming growth factor-β receptor I

MEFs:

mouse embryonic fibroblasts

HNPCC:

hereditary nonpolyposis colorectal cancer

BrdU:

5-bromo-2′-deoxyuridine

TUNEL:

TdT-mediated dUTP-biotin nick-end labeling

References

  • Attisano L, Wrana JL . (2000). Curr Opin Cell Biol 12: 235–243.

  • Bennett V, Baines AJ . (2001). Physiol Rev 81: 1353–1392.

  • Brooks-Wilson AR, Kaurah P, Suriano G, Leach S, Senz J, Grehan N et al. (2004). J Med Genet 41: 508–517.

  • Derynck R, Zhang YE . (2003). Nature 425: 577–584.

  • Dong C, Li Z, Alvarez Jr R, Feng XH, Goldschmidt-Clermont PJ . (2000). Mol Cell 5: 27–34.

  • Ehrlich JS, Hansen MD, Nelson WJ . (2002). Dev Cell 3: 259–270.

  • Fath KR, Trimbur GM, Burgess DR . (1997). J Cell Biol 139: 1169–1181.

  • Guilford P, Hopkins J, Harraway J, McLeod M, McLeod N, Harawira P et al. (1998). Nature 392: 402–405.

  • Hadzija MP, Radosevic S, Kovacevic D, Lukac J, Hadzija M, Spaventi R et al. (2004). Mutat Res 548: 61–73.

  • Kim JB, Islam S, Kim YJ, Prudoff RS, Sass KM, Wheelock MJ et al. (2000). J Cell Biol 151: 1193–1206.

  • Kretzschmar M, Doody J, Timokhina I, Massague J . (1999). Genes Dev 13: 804–816.

  • Li QL, Ito K, Sakakura C, Fukamachi H, Inoue K, Chi XZ et al. (2002). Cell 109: 113–124.

  • Li W, Qiao W, Chen L, Xu X, Yang X, Li D et al. (2003). Development 130: 6143–6153.

  • Mishra L, Cai T, Levine A, Weng D, Mezey E, Mishra B et al. (1998). Int J Dev Biol 42: 221–224.

  • Mishra L, Cai T, Yu P, Monga SP, Mishra B . (1999). Oncogene 18: 353–364.

  • Miyaki M, Iijima T, Kimura J, Yasuno M, Mori T, Hayashi Y et al. (1999). Cancer Res 59: 4506–4509.

  • Muller N, Reinacher-Schick A, Baldus S, van Hengel J, Berx G, Baar A et al. (2002). Oncogene 21: 6049–6058.

  • Nelson WJ, Hammerton RW . (1989). J Cell Biol 108: 893–902.

  • Nelson WJ, Nusse R . (2004). Science 303: 1483–1487.

  • Peinado H, Quintanilla M, Cano A . (2003). J Biol Chem 278: 21113–21123.

  • Piepenhagen PA, Nelson WJ . (1998). Mol Biol Cell 9: 3161–3177.

  • Pinder JC, Baines AJ . (2000). Nature 406: 253–254.

  • Roberts AB, Sporn MB . (1990). The Transforming Growth Factor-βs. Springer-Verlag: Heildelberg.

    Book  Google Scholar 

  • Rosivatz E, Becker I, Specht K, Fricke E, Luber B, Busch R et al. (2002). Am J Pathol 161: 1881–1891.

  • Scartozzi M, Galizia E, Freddari F, Berardi R, Cellerino R, Cascinu S . (2004). Cancer Treat Rev 30: 451–459.

  • Shi Y, Massague J . (2003). Cell 113: 685–700.

  • Siegel PM, Massague J . (2003). Nat Rev Cancer 3: 807–821.

  • Sormunen RT, Leong AS, Vaaraniemi JP, Fernando SS, Eskelinen SM . (1999). J Pathol 187: 416–423.

  • Tang B, Vu M, Booker T, Santner SJ, Miller FR, Anver MR et al. (2003). J Clin Invest 112: 1116–1124.

  • Tang Y, Katuri V, Dillner A, Mishra B, Deng CX, Mishra L . (2003). Science 299: 574–577.

  • Tang Y, Katuri V, Srinivasan R, Fogt F, Redman R, Anand G et al. (2005). Cancer Res 65: 4228–4237.

  • Tsukazaki T, Chiang TA, Davison AF, Attisano L, Wrana JL . (1998). Cell 95: 779–791.

  • Waite KA, Eng C . (2003). Nat Rev Genet 4: 763–773.

  • Xu X, Brodie SG, Yang X, Im YH, Parks WT, Chen L et al. (2000). Oncogene 19: 1868–1874.

  • Yang J, Mani SA, Donaher JL, Ramaswamy S, Itzykson RA, Come C et al. (2004). Cell 117: 927–939.

Download references

Acknowledgements

We thank Dr M Zasloff, Dr R Schlegel and Dr S Baker for critical review of the manuscript, and Dr Eugene A Volpe and Anan H Said for their technical support.

This work was supported by NIH Grants RO1 CA106614A (LM), RO1 DK56111 (LM), RO1 DK58637 (BM), VA Merit Award (LM) and R Robert and Sally D Funderburg Research Scholar (LM).

Author information

Author notes

  1. V Katuri and Y Tang: These authors contributed equally to the work.

Authors and Affiliations

  1. Department of Surgery, Laboratory of Cancer Genetics, Digestive Diseases, and Developmental Molecular Biology, Medicine, Lombardi Cancer Center, Georgetown University, Washington, DC, USA

    V Katuri, Y Tang, W Jogunoori, S Evans, B Mishra & L Mishra

  2. Genetics of Development and Disease Branch, NIDDK, NIH, Bethesda, MD, USA

    C Li & C-X Deng

  3. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    A Rashid

  4. Department of Surgery, Washington, DC, USA

    A N Sidawy & L Mishra

  5. Department of Veterans Affairs, Washington, DC, USA

    A N Sidawy & L Mishra

  6. Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, PA, USA

    E P Reddy

Authors
  1. V Katuri
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Y Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. C Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. W Jogunoori
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. C-X Deng
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A Rashid
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. A N Sidawy
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. S Evans
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. E P Reddy
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. B Mishra
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. L Mishra
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to B Mishra or L Mishra.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Katuri, V., Tang, Y., Li, C. et al. Critical interactions between TGF-β signaling/ELF, and E-cadherin/β-catenin mediated tumor suppression. Oncogene 25, 1871–1886 (2006). https://doi.org/10.1038/sj.onc.1209211

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1209211

Keywords

This article is cited by

Search

Advanced search

Quick links